Abstract
ObjectiveTo determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods.MethodsEleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period.ResultsThe mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1).ConclusionWe determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis.
Highlights
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system, which predominantly affects women, and is most commonly diagnosed in the early adulthood [1, 2]
In this study of NAT-treated highly active relapsing remitting multiple sclerosis (RRMS) patients, therapeutic drug monitoring revealed a low transfer of NAT into breastmilk and a small, non-significant decrease of NAT serum trough concentration across pregnancy
No evidence of clinical and radiological disease activity was detected in NAT exposed pregnancies and postpartum period up to six months, puerperium was linked to a transient sNfL peak in some patients
Summary
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system, which predominantly affects women, and is most commonly diagnosed in the early adulthood [1, 2]. The natural reduction in relapses that occurs especially during the third trimester of pregnancy may not be sufficient to control disease activity, in those pwMS with a highly active disease course [3, 4]. Withdrawal of some of the more highly efficacious disease modifying drugs has been associated with a return or even rebound of disease activity during pregnancy [4–7]. Natalizumab (NAT; Tysabri®, Biogen, Cambridge, MA), as one of the highly efficacious treatments, can be continued in selected patients throughout pregnancy after weighting benefits for the mother against the potential risks to the fetus [8]. NAT is a humanized anti-a4 integrin Immunoglobulin(Ig)G4 antibody that binds the a4-subunit of the a4b1-integrin, preventing leukocyte migration into the central nervous system [9]. Pharmacokinetics (PK) and pharmacodynamics of several drugs are frequently altered during pregnancy. Maternal NAT levels throughout pregnancy and postpartum are still unknown
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